Congruence Mapping of the Activity Flows Allocated in Built Environments: A Pilot Application of Under-Development Software in an Emergency-Care Service

Featured ApplicationThis paper presents the application of a software program that is currently under development that provides feedback for the mapping activities that are carried out in built environments and analyses the congruence in the relationship between the flow of activities and their environments. Exemplary results were obtained in the case study of a healthcare emergency facility, although it is possible to apply this software in other types of complex environments. The obtained data allow facility managers to prioritize and reallocate activities when a change is required. It also shows unmapped relationships. It is important to investigate these data because they can indicate failures in the mapping process and can provide an opportunity to obtain a more complete understanding of the allocation and flow of activities. These data can also help us to identify points of conflict or opportunities for adjustment in the allocation of activities in order to improve the flow of activities.Due to the large number of activities that must be carried out by emergency-care services (ESs), the tasks of facility managers and architects are challenging and complex. Several strategies, guides, and diagnoses have already been developed in order to improve ESs. Part of the solution to this problem depends on obtaining a normative and universal understanding of the problem, and another part depends on conducting a specific and relational analysis between the environment and the flow of activities that are allocated within it. This paper presents the results of a study that was conducted using a software program that is currently under development for mapping the congruence relationship between activities and environments. Here, we present a discussion of the first results that were obtained with the instrument, which was applied to a single case. For this purpose, the fundamentals of the instrument, as well as the environment and the flows of an ES at a university hospital, are described. The forms of analysis, benefits, and limitations of the instrument were investigated, with a view towards its use in supporting the management and the design of large and complex environments, such as emergency departments. In this program, the relationships that are hidden from the managers, the designers, and the researchers due to the aforementioned complexity are revealed through the use of matrices. This mapping can supplement the decision making of the managers and the designers. The application showed advantages in modeling with fewer inputs, mainly in pre-design evaluations.

FDA approved five-membered ring fused pyrimidine-based derivatives and their biological properties

Pyrimidines-based drugs are one of the most important drugs for novel and recurring viruses, including the coronavirus. This chapter deals with 41 FDA-approved five-membered ring fused pyrimidine-based drugs, their synthetic strategies, and pharmacological activities. © 2023 Elsevier Ltd. All rights reserved.

A spatiotemporal spread of COVID-19 pandemic with vaccination optimal control strategy: A case study in Morocco

On March 2, 2020, the Moroccan Ministry of Health announced the first case of COVID-19 in the city of Casablanca for a Moroccan tourist who came from Italy. The SARS-COV-2 virus has spread throughout the Kingdom of Morocco. In this paper, we study the spatiotemporal transmission of the COVID-19 virus in the Kingdom of Morocco. By sup-porting a SIW IHR partial differential equation for the spread of the COVID-19 pandemic in Morocco as a case study. Our main goal is to characterize the optimum order of control-ling the spread of the COVID-19 pandemic by adopting a vaccination strategy, the aim of which is to reduce the number of susceptible and infected individuals without vaccination and to maximize the recovered individuals by reducing the cost of vaccination using one of the vaccines approved by the World Health Organization. To do this, we proved the existence of a pair of control. It provides a description of the optimal controls in terms of state and auxiliary functions. Finally, we provided numerical simulations of data related to the transmission of the COVID-19 pandemic. Numerical results are presented to illustrate the effectiveness of the adopted approach. ©2023 Lviv Polytechnic National University.

Likelihood-Free Dynamical Survival Analysis applied to the COVID-19 epidemic in Ohio.

The Dynamical Survival Analysis (DSA) is a framework for modeling epidemics based on mean field dynamics applied to individual (agent) level history of infection and recovery. Recently, the Dynamical Survival Analysis (DSA) method has been shown to be an effective tool in analyzing complex non-Markovian epidemic processes that are otherwise difficult to handle using standard methods. One of the advantages of Dynamical Survival Analysis (DSA) is its representation of typical epidemic data in a simple although not explicit form that involves solutions of certain differential equations. In this work we describe how a complex non-Markovian Dynamical Survival Analysis (DSA) model may be applied to a specific data set with the help of appropriate numerical and statistical schemes. The ideas are illustrated with a data example of the COVID-19 epidemic in Ohio.

Analysis on Infection Wave and Decay of Transmission Risk Based on Spatial SIR Model - Taking COVID Epidemic as an Example

Starting with the spatial SIR model, this paper gives the strict boundary conditions, and obtains two theorems in the process of infectious disease transmission through theoretical analysis. After that, the partial differential equations are transformed into ordinary differential equations by the method of traveling wave solution, and the solutions of infectious wave velocity and hypergeometric function are further derived. Beside local diffusion operator model, the paper also developed global transmission risk functions as convolution kernels and discovered their properties. The solution of the spatial infectious disease model is visualized by programming, and the influence of parameter changes on the solution is discussed. Finally, some variants of the model in special cases are given. This paper proves that under generalized assumption the three population densities of the spatial SIR model results at the origin cannot take extreme values at the same time, and when the infected density takes extreme values at the origin, the higher-order derivative of the infected density to the space is zero. The hypergeometric function method verifies the solution at infinity of the equations, and the above solution can be used to approximate when the distance from the infection source radius is large. In this paper, the discussion on the impact of the changes of several infectious disease parameters can inspire the methods of epidemic prevention and control.

Chapter 5 - FDA approved five-membered ring fused pyrimidine-based derivatives and their biological properties

Pyrimidines-based drugs are one of the most important drugs for novel and recurring viruses, including the coronavirus. This chapter deals with 41 FDA-approved five-membered ring fused pyrimidine-based drugs, their synthetic strategies, and pharmacological activities.

The Complexity and Multiplicity of the Specific cAMP Phosphodiesterase Family: PDE4, Open New Adapted Therapeutic Approaches.

Cyclic nucleotides (cAMP, cGMP) play a major role in normal and pathologic signaling. Beyond receptors, cyclic nucleotide phosphodiesterases; (PDEs) rapidly convert the cyclic nucleotide in its respective 5'-nucleotide to control intracellular cAMP and/or cGMP levels to maintain a normal physiological state. However, in many pathologies, dysregulations of various PDEs (PDE1-PDE11) contribute mainly to organs and tissue failures related to uncontrolled phosphorylation cascade. Among these, PDE4 represents the greatest family, since it is constituted by 4 genes with multiple variants differently distributed at tissue, cellular and subcellular levels, allowing different fine-tuned regulations. Since the 1980s, pharmaceutical companies have developed PDE4 inhibitors (PDE4-I) to overcome cardiovascular diseases. Since, they have encountered many undesired problems, (emesis), they focused their research on other PDEs. Today, increases in the knowledge of complex PDE4 regulations in various tissues and pathologies, and the evolution in drug design, resulted in a renewal of PDE4-I development. The present review describes the recent PDE4-I development targeting cardiovascular diseases, obesity, diabetes, ulcerative colitis, and Crohn's disease, malignancies, fatty liver disease, osteoporosis, depression, as well as COVID-19. Today, the direct therapeutic approach of PDE4 is extended by developing allosteric inhibitors and protein/protein interactions allowing to act on the PDE interactome.

5-Hydroxymethylcytosine Signatures in Circulating Cell-Free DNA as Early Warning Biomarkers for COVID-19 Progression and Myocardial Injury.

Background: The symptoms of coronavirus disease 2019 (COVID-19) range from moderate to critical conditions, leading to death in some patients, and the early warning indicators of the COVID-19 progression and the occurrence of its serious complications such as myocardial injury are limited. Methods: We carried out a multi-center, prospective cohort study in three hospitals in Wuhan. Genome-wide 5-hydroxymethylcytosine (5hmC) profiles in plasma cell-free DNA (cfDNA) was used to identify risk factors for COVID-19 pneumonia and develop a machine learning model using samples from 53 healthy volunteers, 66 patients with moderate COVID-19, 99 patients with severe COVID-19, and 38 patients with critical COVID-19. Results: Our warning model demonstrated that an area under the curve (AUC) for 5hmC warning moderate patients developed into severe status was 0.81 (95% CI 0.77-0.85) and for severe patients developed into critical status was 0.92 (95% CI 0.89-0.96). We further built a warning model on patients with and without myocardial injury with the AUC of 0.89 (95% CI 0.84-0.95). Conclusion: This is the first study showing the utility of 5hmC as an accurate early warning marker for disease progression and myocardial injury in patients with COVID-19. Our results show that phosphodiesterase 4D and ten-eleven translocation 2 may be important markers in the progression of COVID-19 disease.

American Chemical Society (ACS) – 262nd National Meeting and Exposition

Atlanta, Georgia, was the grand setting of the Fall 2021 American Chemical Society (ACS) National Meeting & Exposition, subheaded ‘Resilience of Chemistry.’ The meeting was both an in-person and virtual meeting at Georgia World Congress Center, and consisted of poster presentations, oral sessions, symposia, press releases and media briefings from s chosen from thousands of scientific presentations on topics that include food and nutrition, medicine, health, energy, the environment, medicinal chemistry, biological chemistry, and other fields where chemistry plays a central role. Presentations were either in person or virtual, or both, allowing for an almost return to normal meeting attendance since the start of the COVID-19 pandemic, with live interaction possible in a room or online.

A MARTINGALE FORMULATION FOR STOCHASTIC COMPARTMENTAL SUSCEPTIBLE-INFECTED-RECOVERED (SIR) MODELS TO ANALYZE FINITE SIZE EFFECTS IN COVID-19 CASE STUDIES

Deterministic compartmental models for infectious diseases give the mean behaviour of stochastic agent-based models. These models work well for counterfactual studies in which a fully mixed large-scale population is relevant. However, with finite size populations, chance variations may lead to significant departures from the mean. In real-life applications, finite size effects arise from the variance of individual realizations of an epidemic course about its fluid limit. In this article, we consider the classical stochastic Susceptible-Infected-Recovered (SIR) model, and derive a martingale formulation consisting of a deterministic and a stochastic component. The deterministic part coincides with the classical deterministic SIR model and we provide an upper bound for the stochastic part. Through analysis of the stochastic component depending on varying population size, we provide a theoretical explanation of finite size effects. Our theory is supported by quantitative and direct numerical simulations of theoretical infinitesimal variance. Case studies of coronavirus disease 2019 (COVID-19) transmission in smaller populations illustrate that the theory provides an envelope of possible outcomes that includes the field data.

A European pharmacotherapeutic agent roflumilast exploring integrated preclinical and clinical evidence for SARS CoV-2 mediated inflammation to organ damage.

COVID-19 has spread globally, affecting almost 160 million individuals. Elderly and pre-existing patients (such as diabetes, heart disease and asthma) seem more susceptible to severe illness with COVID-19. Roflumilast was licensed for usage in the European Union in July 2010 as a phosphodiesterase-4 (PDE4) inhibitor. Under preclinical studies, roflumilast has been shown to decrease bleomycin-induced lung fibrosis, lung hydroxyproline and right heart thickening. The current study reviewed existing data that the PDE-4 inhibitor, a roflumilast, protects renal tissues and other major organ systems after COVID-19 infection by decreasing immune cell infiltration. These immune-balancing effects of roflumilast were related to a decrease in oxidative and inflammatory burden, caspase-3 suppression and increased protein kinase A (PKA)/cyclic A.M.P. (cAMP) levels in renal and other organ tissue.

Analysis of epidemic spread dynamics using a PDE model and COVID-19 data from Hamilton County OH USA

We study the spatiotemporal dynamics of an epidemic spread using a compartmentalized PDE model. The model is validated using COVID-19 data from Hamilton County, Ohio, USA. The model parameters are estimated using a month of recorded data and then used to forecast the infection spread over the next ten days. The model is able to accurately estimate the key dynamic characteristics of COVID-19 spread in the county. Additionally, a stability analysis indicates that the model is robust to disturbances and perturbations which, for instance, could be used to represent the effects of super spreader events. We also use the modeling framework to analyse and discuss the impact of Non-pharmaceutical interventions (NPIs) for mitigation of infection. Our results suggest that such models can yield useful short and medium term predictive characterization of an epidemic spread in a restricted geographical region and also help formulate effective NPIs for mitigation. The results also signify the importance of further research into the accurate analytical representation of specific NPIs and hence their dampening effects on an infection spread. Copyright © 2021 The Authors.

The PDE4 Inhibitor Tanimilast Blunts Proinflammatory Dendritic Cell Activation by SARS-CoV-2 ssRNAs.

Phosphodiesterase 4 (PDE4) inhibitors are immunomodulatory drugs approved to treat diseases associated with chronic inflammatory conditions, such as COPD, psoriasis and atopic dermatitis. Tanimilast (international non-proprietary name of CHF6001) is a novel, potent and selective inhaled PDE4 inhibitor in advanced clinical development for the treatment of COPD. To begin testing its potential in limiting hyperinflammation and immune dysregulation associated to SARS-CoV-2 infection, we took advantage of an in vitro model of dendritic cell (DC) activation by SARS-CoV-2 genomic ssRNA (SCV2-RNA). In this context, Tanimilast decreased the release of pro-inflammatory cytokines (TNF-α and IL-6), chemokines (CCL3, CXCL9, and CXCL10) and of Th1-polarizing cytokines (IL-12, type I IFNs). In contrast to ß-methasone, a reference steroid anti-inflammatory drug, Tanimilast did not impair the acquisition of the maturation markers CD83, CD86 and MHC-II, nor that of the lymph node homing receptor CCR7. Consistent with this, Tanimilast did not reduce the capability of SCV2-RNA-stimulated DCs to activate CD4+ T cells but skewed their polarization towards a Th2 phenotype. Both Tanimilast and ß-methasone blocked the increase of MHC-I molecules in SCV2-RNA-activated DCs and restrained the proliferation and activation of cytotoxic CD8+ T cells. Our results indicate that Tanimilast can modulate the SCV2-RNA-induced pro-inflammatory and Th1-polarizing potential of DCs, crucial regulators of both the inflammatory and immune response. Given also the remarkable safety demonstrated by Tanimilast, up to now, in clinical studies, we propose this inhaled PDE4 inhibitor as a promising immunomodulatory drug in the scenario of COVID-19.

Novel Therapeutic Approaches to Psoriasis and Risk of Infectious Disease.

Psoriasis is a chronic immune-mediated skin and joint disease, with a plethora of comorbidities, characterized by a certain genetic predisposition, and a complex pathogenesis based on the IL-23/IL-17 pathway. There is no doubt that the patients affected by psoriasis are more susceptible to infections as well as that the risk of infection is higher in psoriatic subjects than in the general population. The advent of biotechnological agents on the therapeutic arsenal actually available for the treatment of moderate-to-severe patients, given the fact that the severity of the disease is a predictor of the level of infectious risk, has raised the question of whether these 'new' drugs could be considered a safer option and how they can be used in selected cases. Old and newer strategies in cases of chronic infectious conditions are reviewed under the light of clinical trials and other studies present in literature.

Pulmonary artery targeted therapy in treatment of COVID-19 related ARDS. Literature review.

INTRODUCTION: The most grievous complication of the COVID-19 is the acute respiratory distress syndrome. A specific, rescue treatment for rapidly deteriorating patients should emerge to improve respiratory function and help patients to survive the most challenging period. Drugs used in targeted therapy of pulmonary arterial hypertension (PAH) appears to be suitable for this task and this article describes their potential for treatment of severe cases of COVID-19. METHODS: The authors reviewed the following databases for randomized controlled trials, reviews and meta-analyses published up to July 2020: Pubmed, Scopus, Google Scholar, Cochrane Database and ClinicalKey. The authors included every study contributory to the assessment of the potential of drugs used in targeted PAH therapy in treatment of COVID-19. RESULTS: Endothelin receptor antagonists, phosphodiesterase 5 inhibitors, riociguat and prostacyclin have proven ani-inflammatory effect and reduce pulmonary artery blood pressure, lung oedema and remodelling. Bosentan shows antiviral properties and sildenafil, as well as epoprostenol, inhibits apoptosis of lung epithelial cells. Among patients with lung lesions the decrease of pulmonary blood pressure can lead to increase of ventilation/perfusion mismatch and decrease of blood oxygenation. CONCLUSIONS: Among all assessed drugs bosentan, sildenafil and epoprostenol appear to be most promising and a combination of these drugs should be considered due to synergism. The targeted PAH therapy in treatment of COVID-19 associated ARDS could be a useful tool saving lives of patients with severe SARS-CoV-2 infection, however, its introduction should be investigated and monitored very carefully as it can lead to transient deterioration of patient condition.

CuCl2-catalyzed inexpensive, faster and ligand/additive free synthesis of isoquinolin-1(2H)-one derivatives via the coupling-cyclization strategy: Evaluation of a new class of compounds as potential PDE4 inhibitors.

In spite of possessing a wide range of pharmacological properties the anti-inflammatory activities of isoquinolin-1(2H)-ones were rarely known or explored earlier. PDE4 inhibitors on the other hand in addition to their usefulness in treating inflammatory diseases have been suggested to attenuate the cytokine storm in COVID-19 especially TNF-α. In our effort, a new class of isoquinolin-1(2H)-ones derivatives containing an aminosulfonyl moiety were designed and explored as potential inhibitors of PDE4. Accordingly, for the first time a CuCl2-catalyzed inexpensive, faster and ligand/additive free approach has been developed for the synthesis of these predesigned isoquinolin-1(2H)-one derivatives via the coupling-cyclization strategy. Thus, the CuCl2-catalyzed reaction of 2-iodobenzamides with appropriate terminal alkynes proceeded with high chemo and regioselectivity affording the desired compounds in 77-84% yield within 1-1.5 h. The methodology also afforded simpler isoquinolin-1(2H)-ones devoid of aminosulfonyl moiety showing a broader generality and scope of this approach. Several of the synthesized compounds especially 3c, 3k and 3s showed impressive inhibition (83-90%) of PDE4B when tested at 10 µM in vitro whereas compounds devoid of aminosulfonyl moiety was found to be less active. In spite of high inhibition showed at 10 µM these compounds did not show proper concertation dependent inhibition below 1 µM that was reflected in their IC50 values e.g. 2.43 ± 0.32, 3.26 ± 0.24 and 3.63 ± 0.80 µM for 3k, 3o and 3s respectively. The anti-inflammatory potential of these compounds was indicated by their TNF-α inhibition (60-50% at 10 µM). The in silico docking studies of these molecules suggested good interactions with PDE4B and selective inhibition of PDE4B by 3k over PDE4D that was supported by in vitro assay results. These observations together with the favorable ADME and safety predicted for 3kin silico not only suggested 3k as an interesting hit molecule for further studies but also reveal the first example of isoquinolin-1(2H)-one based inhibitor of PDE4B.

Gut probiotic Lactobacillus rhamnosus attenuates PDE4B-mediated interleukin-6 induced by SARS-CoV-2 membrane glycoprotein.

Membrane glycoprotein is the most abundant protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but its role in coronavirus disease 2019 (COVID-19) has not been fully characterized. Mice intranasally inoculated with membrane glycoprotein substantially increased the interleukin (IL)-6, a hallmark of the cytokine storm, in bronchoalveolar lavage fluid (BALF), compared to mice inoculated with green fluorescent protein (GFP). The high level of IL-6 induced by membrane glycoprotein was significantly diminished in phosphodiesterase 4 (PDE4B) knockout mice, demonstrating the essential role of PDE4B in IL-6 signaling. Mycelium fermentation of Lactobacillus rhamnosus (L. rhamnosus) EH8 strain yielded butyric acid, which can down-regulate the PDE4B expression and IL-6 secretion in macrophages. Feeding mice with mycelia increased the relative abundance of commensal L. rhamnosus. Two-week supplementation of mice with L. rhamnosus plus mycelia considerably decreased membrane glycoprotein-induced PDE4B expression and IL-6 secretion. The probiotic activity of L. rhamnosus plus mycelia against membrane glycoprotein was abolished in mice treated with GLPG-0974, an antagonist of free fatty acid receptor 2 (Ffar2). Activation of Ffar2 in the gut-lung axis for down-regulation of the PDE4B-IL-6 signalling may provide targets for development of modalities including probiotics for treatment of the cytokine storm in COVID-19.

PdCl2-catalyzed synthesis of a new class of isocoumarin derivatives containing aminosulfonyl / aminocarboxamide moiety: First identification of a isocoumarin based PDE4 inhibitor.

While anti-inflammatory properties of isocoumarins are known their PDE4 inhibitory potential was not explored previously. In our effort the non-PDE4 inhibitor isocoumarins were transformed into the promising inhibitors via introducing an aminosulfonyl/aminocarboxamide moiety to the C-3 benzene ring attached to the isocoumarin framework. This new class of isocoumarins were synthesized via a PdCl2-catalyzed construction of the 4-allyl substituted 3-aryl isocoumarin ring starting from the appropriate 2-alkynyl benzamide derivative. Several compounds showed good inhibition of PDE4B in vitro and the SAR indicated superiority of aminosulfonamide moiety over aminocarboxamide in terms of PDE4B inhibition. Two compounds 3q and 3u with PDE4B IC50 = 0.43 ± 0.11 and 0.54 ± 0.19 µM and ≥ 2-fold selectivity over PDE4D emerged as initial hits. The participation of aminosulfonamide moiety in PDE4B inhibition and the reason for selectivity though moderate shown by 3q and 3u was revealed by the in silico docking studies. In view of potential usefulness of moderately selective PDE4B inhibitors the compound 3u (that showed PDE4 selectivity over other PDEs) was further evaluated in adjuvant induced arthritic rats. At an intraperitoneal dose of 30 mg/kg the compound showed a significant reduction in paw swelling (in a dose dependent manner), inflammation and pannus formation (in the knee joints) as well as pro-inflammatory gene expression/mRNA levels and increase in body weight. Moreover, besides its TNF-α inhibition and no significant toxicity in an MTT assay the compound did not show any adverse effects in a thorough toxicity studies e.g. teratogenicity, hepatotoxicity, cardiotoxicity and apoptosis in zebrafish. Thus, the isocoumarin 3u emerged as a new, safe and moderately selective PDE4B inhibitor could be useful for inflammatory diseases possibly including COVID-19.

PDE3-inhibitor enoximone prevented mechanical ventilation in patients with SARS-CoV-2 pneumonia.

BACKGROUND: Standard care in severe SARS-CoV-2 pneumonia complicated by severe dyspnea and respiratory failure, consists of symptom reduction, ultimately supported by mechanical ventilation. Patients with severe SARS-CoV-2, a prominent feature of COVID-19, show several similar symptoms to Critical Asthma Syndrome (CAS) patients, such as pulmonary edema, mucus plugging of distal airways, decreased tissue oxygenation, (emergent) exhaustion due to severe dyspnea and respiratory failure. Prior application of elective phosphodiesterase (PDE)3-inhibitors milrinone and enoximone in patients with CAS yielded rapid symptomatic relief and reverted the need for mechanical ventilation, due to their bronchodilator and anti-inflammatory properties. Based on these observations, we hypothesized that enoximone may be beneficial in the treatment of patients with severe SARS-CoV-2 pneumonia and prominent CAS-features. METHODS: In this case report enoximone was administered to four consecutive patients (1 M; 3 F; 46-70 y) with emergent respiratory failure due to SARS-CoV-2 pneumonia. Clinical outcome was compared with three controls who received standard care only. RESULTS: After an intravenous bolus of enoximone 20 mg followed by 10 mg/h via perfusor, a rapid symptomatic relief was observed: two out of four patients recovered within a few hours, the other two (with comorbid COPD GOLD II/III) responded within 24-36 h. Compared to the controls, in the enoximone-treated patients respiratory failure and further COVID-19-related deterioration was reverted and mechanical ventilation was prevented, leading to reduced hospital/ICU time. DISCUSSION: Our preliminary observations suggest that early intervention with the selective PDE3-inhibitor enoximone may help to revert respiratory failure as well as avert mechanical ventilation, and reduces ICU/hospital time in patients with severe SARS-CoV-2 pneumonia. Our findings warrant further research on the therapeutic potential of PDE3-inhibition, alone or in combination with other anti-COVID-19 strategies.